1. Field of the Invention
The present invention relates to a method of delivery of medical devices to patients, especially a method where (e.g., neurological) devices are delivered using nonlinear magnetic stereotaxis in conjunction with non-invasive MR imaging observation techniques such as magnetic resonance imaging, and most especially where drug delivery by said devices is accomplished under real time, non-invasive observation techniques such as magnetic resonance imaging which can indicate metabolic responses to the delivered drug and/or changes in soluble/dispersed concentrations of materials within liquids and/or tissue of a patient in real time or near real time. The present invention also generally relates to medical devices which are compatible with those and other procedures performed during magnetic resonance imaging (MRI), and particularly to medical devices which can deliver drugs during procedures viewed with magnetic resonance (MR) imaging techniques.
2. Background of the Prior Art
The concept of administering minimally invasive therapy and especially minimally invasive drug delivered therapy follows recent trends in medical and surgical practice towards increasing simplicity, safety, and therapeutic effectiveness. Image-guided, minimally invasive therapies have already superseded conventional surgical methods in several procedures. For example, transvascular coronary angioplasty is often now an alternative to open-heart surgery for coronary artery bypass, and laparascopic cholecystectomy is often an alternative to major abdominal surgery for gall bladder removal. The use of the less invasive techniques has typically reduced hospital stays by 1–2 weeks and the convalescence periods from 1–2 months to 1–2 weeks.
While endoscopic, arthroscopic, and endovascular therapies have already produced significant advances in health care, these techniques ultimately suffer from the same limitation. This limitation is that the accuracy of the procedure is “surface limited” by what the surgeon can either see through the device itself or otherwise visualize (as by optical fibers) during the course of the procedure. That is, the visually observable field of operation is quite small and limited to those surfaces (especially external surfaces of biological masses such as organs and other tissue) observable by visible radiation, due to the optical limitations of the viewing mechanism. MR imaging, by comparison, overcomes this limitation by enabling the physician or surgeon to non-invasively visualize tissue planes and structures (either in these planes or passing through them) beyond the surface of the tissue under direct evaluation. Moreover, MR imaging enables differentiation of normal from abnormal tissues, and it can display critical structures such as blood vessels in three dimensions. Prototype high-speed MR imagers which permit continuous real-time visualization of tissues during surgical and endovascular procedures have already been developed. MR-guided minimally invasive therapy is expected to substantially lower patient morbidity because of reduced post-procedure complications and pain. The use of this type of procedure will translate into shorter hospital stays, a reduced convalescence period before return to normal activities, and a generally higher quality of life for patients. The medical benefits and health care cost savings are likely to be very substantial.
A specific area where research is moving forward on advances of this type is in the treatment of neurological disorders. Specifically, the advent of new diagnostic and therapeutic technologies promises to extend the utility of intracerebral drug delivery procedures and thus possibly advance the efficacy of existing and/or planned treatments for various focal neurological disorders, neurovascular diseases and neurodegenerative processes. Currently, when the standard procedure requires neurosurgeons or interventional neuroradiologists to deliver drug therapy into the brain, the drug delivery device, such as a catheter, must either be passed directly through the intraparenchymal tissues to the targeted region of the brain, or guided through the vasculature until positioned properly. An important issue in either approach is the accuracy of the navigational process used to direct the movement of the drug delivery device. In many cases, the physical positioning of either part or all of the catheter's lumen within the brain is also important as, for example, in situations where a drug or some other therapeutic agent will be either infused or retroperfused into the brain through the wall or from the tip of the catheter or other drug delivery device.
New technologies like intra-operative magnetic resonance imaging and nonlinear magnetic stereotaxis, the latter discussed by G. T. Gillies, R. C. Ritter, W. C. Broaddus, M. S. Grady, M. A. Howard III, and R. G. McNeil, “Magnetic Manipulation Instrumentation for Medical Physics Research,” Review of Scientific Instruments, Vol. 65, No. 3, pp. 533–562 (March 1994), as two examples, will likely play increasingly important roles here. In the former case, one type of MR unit is arranged in a “double-donut” configuration, in which the imaging coil is split axially into two components. Imaging studies of the patient are performed with this system while the surgeon is present in the axial gap and carrying out procedures on the patient. A second type of high-speed MR imaging system combines high-resolution MR imaging with conventional X-ray fluoroscopy and digital subtraction angiography (DSA) capability in a single hybrid unit. These new generations of MR scanners are able to provide the clinician with frequently updated images of the anatomical structures of interest, therefore making it possible to tailor a given interventional procedure to sudden or acute changes in either the anatomical or physiological properties of, e.g., a part of the brain into which a drug agent is being infused.
Nonlinear magnetic stereotaxis is the image-based magnetically guided movement of a small object directly through the bulk brain tissues or along tracts within the neurovasculature or elsewhere within the body. Electromagnets are used to magnetically steer the implant, giving (for example) the neurosurgeon or interventional neuroradiologist the ability to guide the object along a particular path of interest. (The implant might be either magnetically and/or mechanically advanced towards its target, but is magnetically steered, in either case. That is, magnetic fields and gradients are used to provide torques and linear forces to orient or shift the position of the implant or device, with a mechanical pushing force subsequently providing none, some, or all of the force that actually propels the implant or device. Additional force may be provided magnetically.) The implant's position is monitored by bi-planar fluoroscopy, and its location is indicated on a computerized atlas of brain images derived from a pre-operative MR scan. Among other applications, the implant might be used to tow a pliable catheter or other drug delivery device to a selected intracranial location through the brain parenchyma or via the neurovasculature. Magnetic manipulation of catheters and other probes is well documented in research literature. For example, Cares et al. (J. Neurosurg, 38:145, 1973) have described a magnetically guided microballoon released by RF induction heating, which was used to occlude experimental intracranial aneurysms. More recently, Kusunoki et al. (Neuroradiol 24: 127, 1982) described a magnetically controlled catheter with cranial balloon useful in treating experimental canine aneurysms. Ram and Meyer (Cathet. Cardiovas. Diag. 22:317, 1991) have described a permanent magnet-tipped polyurethane angiography catheter useful in cardiac interventions, in particular intraventricular catheterization in neonates.
U.S. Pat. No. 4,869,247 teaches the general method of intra parenchymal and other types of magnetic manipulation, and U.S. Pat. Nos. 5,125,888; 5,707,335; and 5,779,694 describe the use of nonlinear magnetic stereotaxis to maneuver a drug or other therapy delivery catheter system within the brain. U.S. Pat. No. 5,654,864 teaches a general method of controlling the operation of the multiple coils of a magnetic stereotaxis system for the purpose of maneuvering an implant to precisely specified locations within the body.
Both of these technologies offer a capability for performing image-guided placement of a catheter or other drug delivery device, thus allowing drug delivery directly into the brain via infusion through the walls of the catheter or out flow of the tip off the catheter. In the case of drug delivery directly into the brain tissues, the screening of large molecular weight substances by the endothelial blood-brain barrier can be overcome. In the case of infusions into specific parts of the cerebrovasculature, highly selective catheterizations can be enabled by these techniques. In either case, however, detailed visual images denoting the actual position of the drug delivery device within the brain would be extremely useful to the clinician in maximizing the safety and efficacy of the procedure. The availability of an MR-visible drug delivery device combined with MR-visible drug agents would make it possible to obtain near real-time information on drug delivery during interventional procedures guided by non-linear magnetic stereotaxis. Drug delivery devices, such as catheters, that are both MR-visible and radio-opaque could be monitored by two modalities of imaging, thus making intra-operative verification of catheter location possible during nonlinear magnetic stereotaxis procedures. (Intra-operative MR assessment might require the temporary removal of the magnetic tip of the drug delivery catheter and interruption of the magnetic stereotaxis procedure to image the patient.).
The geometry and magnetic strength of the magnetic tip will depend upon the particular type of catheter or medical device with which the tip is being used. In a preferred embodiment, the tip would have as small a maximum dimension as would be consistent with maintaining sufficient magnetic dipole moment to couple satisfactorily to the external magnetic fields and gradients used to apply torques and forces to the tip for the purpose of steering or moving the catheter or other medical device. It is preferred that the magnetic element (e.g., a distinct magnetic bead or seed or wire) or the magnetic tip have a maximum dimension of at least 0.5 mm, preferably from 0.5 to 8 mm, more preferably from about 1.0 to 6 mm, and most preferably from about 2 to 5 or 6 mm. To that end, the tip might be made of a permanently magnetic or magnetically permeable material, with compounds of Nd—B—Fe being exemplary, as well as various iron alloys (ferrites and steel alloys). The magnetic tip may be fixed to the distal end of the catheter in any number of ways, depending in part upon the method of use of the catheter, the specific type of catheter, the procedures and the use of the catheter. In one design, the magnetic tip might simply be a small spherical or oblate spheroid of magnetic material (e.g., having a geometry where the semi-major axis is from 1.1 to 3 times longer, preferably from 1.5 to 2.0 or 2.5 time longer than the semi-minor axis). The magnetic tip may be originally fixed to the distal end of the catheter or medical device or passed through the length of the catheter so that it abuts against the interal distal end of the catheter (as a foot would abut the end of a sock). As noted, the magnetic tip may be fixed in place either on the inside, outside or embedded within the composition of the distal end of the catheter or medical device. In a preferred embodiment, the magnetic tip may be thermally, solubly, mechanically, electronically or otherwise removably attached to and separable from the distal end of the catheter or medical device. A heat soluble link is taught in U.S. Pat. No. 5,125,888.
In still another embodiment, the magnetic tip would constitute a plug in the end of an otherwise open-ended catheter, and the tip might either have an open bore along its axis, a plurality of open bores along its axis, or a single or plural configuration of holes along the side of the magnetic tip, any of which openings would be used to facilitate drug delivery from the catheter or to serve as an exit port for the delivery of some other therapy or device into a body part, such as the parenchymal tissues and/or the cerebrobasculature of the brain. Alternatively, the magnetic tip might simply constitute a solid plug that seals the end of the catheter. The distal end of the catheter at which the magnetic tip is placed must be configured such that axial forces and torques applied by either magnetic fields and gradients or by a guide wire internal to the catheter allow said distal end and magnetic tip to be propelled towards a target site with the body, and to do so without said distal end and magnetic tip separating from each other in an inappropriate way and/or at an undesired time or under undesired circumstances. If the magnetic tip must be removed, or detached and removed, prior to MR imaging of the patient, such a procedure could be accomplished by the method taught in U.S. Pat. Nos. 5,125,888; 5,707,335; and 5,779,694, which call for dissolving a heat separable link between the tip and the catheter by a pulse of radio-frequency energy. An alternative means of removing the magnetic tip is discussed by M. A. Howard et al. in their article, “Magnetically Guided Stereotaxis,” in Advanced Neurosurgical Navigation, edited by E. Alexander III and R. J. Maciunas (Thieme Medical Publisher, New York, 1998), which calls for withdrawing the magnetic tip from along the inside of the catheter that it has just steered into place within the body. Without removal of the magnetic tip from the catheter, whole body magnetic forces might be produced on it by the field of the MR imaging system, and these could cause undesired movement of the catheter that it has just steered into place within the body.
In the treatment of neurological diseases and disorders, targeted drug delivery can significantly improve therapeutic efficacy, while minimizing systemic side-effects of the drug therapy. Image-guided placement of the tip of a drug delivery catheter directly into specific regions of the brain can initially produce maximal drug concentration close to some targeted loci of tissue receptors following delivery of the drug. At the same time, the limited distribution of drug injected from a single catheter tip presents other problems. For example, the volume flow rate of drug delivery must be very low to avoid indiscriminate hydrodynamic damage or other damage to brain cells and nerve fibers. Delivery of a drug from a single point source may also limit the distribution of the drug by decreasing the effective radius of penetration of the drug agent into the surrounding tissue receptor population. Positive pressure infusion, i.e., convection-enhanced delivery of drugs into the brain, as taught by U.S. Pat. No. 5,720,720 may overcome the problem of effective radius of penetration. Also, U.S. patent application Ser. No. 08/857,043, filed on May 15, 1997 and titled “Method and Apparatus for Use with MR Imaging” describes a technology invented in-part by one of the present inventors comprising a method for observing the delivery of material to tissue in a living patient comprising the steps of a) observing by magnetic resonance imaging a visible image within an area or volume comprising tissue of said living patient, the area or volume including a material delivery device, b) delivering at least some material by the material delivery device into the area or volume comprising tissue of a living patient, and c) observing a change in property of said visible image of the area or volume comprising tissue of a living patient while said material delivery device is still present within the area or volume. This process, including the MRI visualization, is performed in approximately or actually real time, with the clinical procedure being guided by the MRI visualization.
Research on magnetic catheterization of cerebral blood vessels generally has focused on design of transvascular devices to thrombose aneurysms, to deliver cytotaxic drugs to tumors, and to deliver other therapies without the risks of major invasive surgery. Examples of such studies include Hilal et al (J. Appl. Phys. 40:1046, 1969), Molcho et al (IEEE Trans. Biomed. Eng. BME-17, 134, 1970), Penn et al (J. Neurosurg. 38:239, 1973), and Hilal et al (Radiology 113:529,1974).
U.S. Pat. Nos. 4,869,247, 5,654,864, 5,125,888, 5,707,335 and 5,779,694 describe processes and apparatus for the use of magnetic stereotaxis for the manipulation of an object or implant which is moved into position within a patient, particularly within the cranial region and specifically within the brain but in principle elsewhere in the body also. These patents do no not involve any contemplation of real time visualization of drug distribution within the brain, especially by MRI. It should be noted that the potential exists for interactive interference between the two systems, magnetic resonance imaging and magnetic stereotaxis, particularly where fine images are being provided by a system based on magnetic coils, especially as described in U.S. patent application Ser. No. 08/916,596, filed on Aug. 22, 1997, which is incorporated herein by reference for its disclosure of the design, construction, structure and operation of coils and catheters in MR-guided procedures. That application describes medical devices which are compatible with procedures performed during magnetic resonance imaging (MRI), and particularly to medical devices which can deliver drugs during procedures viewed with magnetic resonance (MR) imaging techniques.
Medical procedures may now be performed on areas of the patient which are relatively small. Procedures may be performed on small clusters of cells, within veins and arteries, and in remote sections of the body with minimally invasive techniques, such as without surgical opening of the body. As these procedures, such as balloon angioplasty, microsurgery, electrotherapy, and drug delivery are performed within the patient with minimally invasive techniques without major surgical opening of the patient, techniques have had to be developed which allow for viewing of the procedure concurrent with the procedure. X-ray imaging, such as X-ray fluoroscopy, is a possible method of providing a view of the procedural area, but X-ray exposure for any extended period of time is itself harmful to the patient. Fiber optic viewing of the area does not provide any harmful radiation to the patient, but the fiber optics may take up too large a space to provide both the light necessary for viewing and a path for return of the light, and does not permit beyond the surface imaging (that is, only the surfaces of internal objects may be viewed from the position where the fiber optic device is located). Fiber optics or direct light viewing is more acceptable for larger area medical procedures such as gastroenterological procedures than for more microscopic procedures such as intraparenchymal drug delivery or endovascular drug delivery or procedures.
Techniques have been developed for relatively larger area viewing of MR-compatible devices within a patient by the use of MR-receiver coils in the devices which are tracked by MR imaging systems. Little by way of specific design considerations have been given to devices which have MR viewing capability and specific treatment functions, and especially where the relationship of specific types of treatment and the MR receiver coils must be optimized both for a treatment process and for MR viewing ability.
U.S. Pat. No. 5,211,165 describes a tracking system to follow the position and orientation of an invasive device, and especially a medical device such as a catheter, using radio frequency field gradients. Detection of radio frequency signals is accomplished with coils having sensitivity profiles which vary approximately linearly with position. The invasive device has a transmit coil attached near its end and is driven by a low power RF source to produce a dipole electromagnetic field that can be detected by an array of receive coils distributed around an area of interest of the subject. This system places the transmit coils within the subject and surrounds the subject with receive coils.
U.S. Pat. No. 5,271,400 describes a tracking system to monitor the position and orientation of an invasive device within a subject. The device has an MR active sample and a receiver coil which is sensitive to magnetic resonance signals generated by the MR active sample. These signals are detected in the presence of magnetic field gradients and thus have frequencies which are substantially proportional to the location of the coil along the direction of the applied gradient. Signals are detected responsive to sequentially applied mutually orthogonal magnetic gradients to determine the device's position in several dimensions. The invasive devices shown in FIGS. 2a and 2b and rf coil and an MR active sample incorporated into a medical device and an MR active sample incorporated into a medical device, respectively.
U.S. Pat. No. 5,375,596 describes a method and apparatus for determining the position of devices such as catheters, tubes, placement guidewires and implantable ports within biological tissue. The devices may contain a transmitter/detector unit having an alternating current radio-frequency transmitter with antenna and a radio signal transmitter situated long the full length of the device. The antennae are connected by a removable clip to a wide band radio frequency (RF) detection circuit, situated within the transmitter/detector unit.
U.S. Pat. No. 4,572,198 describes a catheter for use with NMR imaging systems, the catheter including a coil winding for exciting a weak magnetic field at the tip of the catheter. A loop connecting two conductors supports a dipole magnetic field which locally distorts the NMR image, providing an image cursor on the magnetic resonance imaging display.
U.S. Pat. No. 4,767,973 describes systems and methods for sensing and movement of an object in multiple degrees of freedom. The sensor system comprises at least one field-effect transistor having a geometric configuration selected to provide desired sensitivity.
Published PCT Applications WO 93/15872, WO 93/15874, WO 93/15785, and WO 94/27697 show methods of forming tubing, including kink resistant tubing and catheters in which the catheters may contain reinforcing coils. Layer(s) of reinforcing materials may be deposited on and over the reinforcing coils.
U.S. Pat. Nos. 5,451,774 and 5,270,485 describes a three-dimensional circuit structure including a plurality of elongate substrates positioned in parallel and in contact with each other. Electrical components are formed on the surfaces of the substrates, along with electrical conductors coupled to those components. The conductors are selectively positioned on each substrate so as to contact conductors on adjacent substrates. The conductor patterns on the substrates may be helical, circumferential, or longitudinal. Radio frequency signaling between substrates would be effected with a transmitting antenna and a receiving antenna, with radio frequency signal transmitting and receiving circuitry present in the substrates (e.g., column 7, lines 32–43). Circulation of cooling fluid within the device is shown.
U.S. Pat. No. 5,273,622 describes a system for the fabrication of microstructures (including electronic microcircuitry) and thin-film semiconductors on substrates, especially continuous processes for use on elongate substrates such as fibers or filaments.
U.S. Pat. Nos. 5,106,455 and 5,269,882 describes a method and apparatus for fabrication of thin film semiconductor devices using non-planar exposure beam lithography. Circuitry formed on cylindrical objects is shown.
U.S. Pat. No. 5,167,625 describes a multiple vesicle implantable drug delivery system which may contain an electrical circuit which is responsive to signals (including radio signals) which can be used to effect drug delivery.
PCT Application WO 96/33761 (filed 15 Apr. 1996) describes an intraparenchymal infusion catheter system for delivering drugs or other agents comprising a pump coupled to the catheter. A porous tip is disposed at a distal end of the catheter, the tip being porous to discharge an agent or dug at a selected site. The catheter may be customized during use by an expandable portion of the catheter system.
Martin, A. J., Plewes, D. B. and Henkelman, R. M. in “MR Imaging of Blood Vessels with an Intravascular Coil,” J. Mag. Res. Imag., 1992, 2, No. 4, pp. 421–429 describes a method for producing high-resolution magnetic resonance (MR) images of blood vessel walls using a theoretic receiver-coil design based on two coaxial solenoids separated by a gap region and with the current driven in opposite directions. The coils had diameters ranging from 3 to 9 mm. FIG. 3b appears to indicate that sensitivity decreases as the coils diameter moved from 9 to 7 to 5 to 3 mm. Investigation of the Q value of opposed loop and opposed solenoid coils indicated that opposed loop coils displayed low W values and that there was a general trend of lower Q values at smaller Q diameters among the opposed solenoid designs. Within the range investigated, it was stated that a compromise exists between the use of thicker wire for improved performance and thinner wire to limit the overall coil dimensions. Decoupling circuitry is also shown to be useful in performing the imaging functions with this catheter based system in MR imaging.
Hurst, G. C., Hua, J., Duerk, J. I. and Choen, A. M., “Intravascular (Catheter) NMR Receiver Probe: Preliminary Design Analysis and Application in Canine Iliofemoral Imaging,” Magn. Res. In Imaging, 24, 343–357 (1992) explores the feasibility of a catheter-based receiver probe for NMR study of arterial walls. Various potential designs, including opposed solenoids (e.g., FIG. 2b and FIG. 3 a and b) are examined. The catheter probe shown in FIG. 3 was constructed with five turns of 28 gauge wire per solenoid, with 7.5 mm between solenoids and nominal solenoid diameters of 2.8 mm, with the probe resonating at 64 MHz with a 110-pf capacitor.
A device is described for use within an organism, said device may comprise an element having at least one pair of opposed RF receiver microcoils having a space between each microcoil of said pair of microcoils, the coils of said microcoils having diameters of less than 2.4 mm. The device may comprise a catheter having at least one lumen, where the at least one pair of microcoils is radially located about the at least one lumen and the coils have diameters of greater than 0.1 mm and less than 2.4 mm. The device may have no ports or at least one drug delivery port present within said device. The least one drug delivery port may be located so that at least some drug which is delivered through said port is delivered away from said device within said space between said microcoils. The delivery ports may comprise microcatheters present within said device which extend outside of said device to deliver at least some liquid material within a volume bordered by planes extending radially from the catheter at ends of the at least one pair of microcoils which define the space between each microcoil within said at least one pair of microcoils. The device, in response to radio frequency transmission, may generate a field which has an average strength within said volume than in comparable size volumes surrounding said catheter which are radially located directly over each of said microcoils. The at least one pair of microcoils preferably is embedded within a binder material which surrounds said lumen. The at least one pair of microcoils is electrically connected to a preamplifier within a portion of said device which may be inserted into an organism. Where electrical connections are present within said device, it is preferred that at least some of said electrical connections have been formed in situ within said device.
This invention provides a method and object for selective intraparenchymal and/or neuroendovascular drug delivery and other concurrent medical treatment of abnormalities of the human central nervous system concurrent with nonlinear magnetic stereotaxis combined with magnetic resonance (MR) imaging and/or x-ray guidance.
Magnetic Resonance Imaging (MRI) is used in combination with 1) an MR observable delivery device or 2) an MR observable medical device which can alter a water based molecular environment by performed medical operations, the delivery device or medical device being used in the presence of MR observable (in water, body fluid or tissue) compound(s) or composition(s). MRI images are viewed with respect to a molecular environment to determine the position of the delivery device or medical device (hereinafter collectively referred to as the “delivery device” unless otherwise specifically identified) and changes in the environment where the delivery device is present as an indication of changes in the molecular environment. As the delivery of material from the delivery device is the most MR visible event within the molecular environment in the vicinity of the delivery area, the changes in the molecular environment are attributable to the delivery of the MR observable compounds or compositions. Changes in signal properties, such as changes in the signal intensity within the MR images reflect the changes in the molecular environment and therefore track the location of delivered materials, and are indicative of delivery rates and delivery volumes in viewable locations. With the medical device, chemical composition within the molecular environment may also be altered as by the removal of deposits of certain materials into the liquid (water) environment or stimulated activity of tissue to release materials, where those materials can alter the MR response. Some materials that may be removed by medical procedures will not affect the MR response, such as calcium, but fatty materials may affect the response. Additionally, medical treatments which stimulate natural activities of chemical producing systems (e.g., the glands, organs and cells of the body which generate chemicals such as enzymes and other chemicals with specific biological activity [e.g., dopamine, insulin, etc.]) can be viewed under direct MR observation and any changes in chemical synthetic activity and/or delivery can be observed because of molecular environment changes which occur upon increased synthetic activity.
One recently established method of reading the data obtained from the MR imaging is technically founded upon existing knowledge of Apparent Diffusion Coefficients (ADC) in particular regions of the body. There is significant published literature with respect to ADC values for specific tissues in various parts of animals, including various tissues of humans (e.g., Joseph V. Hajnal, Mark Doran, et al., “MR Imaging of Anisotropically Restricted Diffusion of Water in the Nervous System: Technical, Anatomic, and Pathological Considerations,” Journal of Computer Assisted Tomography, 15(I): 1–18, January/February, 1991, pp. 1–18). It is also well established in the literature that loss of tissue structure through disease results in a decrease of the ADC, as the tissue becomes more like a homogeneous suspension. Clinical observations of changes in diffusion behavior have been made in various tissue cancers, multiple sclerosis, in strokes (where the reduction in diffusion precedes the increase in T2), and in epilepsy. (e.g., Y. Hasegawa, L. Latour, et al. “Temperature Dependent Change of Apparent Diffusion Coefficient of Water in Normal Ischemic Brain”, Journal of Cerebral Blood Flow and Metabolism 14:389–390, 1994). Thus, ADC values are specific for specific types of tissues. Accordingly, as different drugs/chemicals are introduced into a tissue volume under MR observation, the change in ADC resulting from each drug/chemical interaction with the ambient water proton environment can be observed.
While the ADC is the preferred means within the present invention of mapping the delivery of drug in tissue, other embodiments of the invention allow for additional tissue contrast parameters to track the delivery of a drug into tissue. In other words, the delivery of a drug into tissue will cause other MRI-observable changes which can be mapped (as is done for ADC) and which can be used to map the spatial distribution characteristics of the drug within and around the targeted tissue. While some of these observations may be larger in magnitude than others, any of the MRI contrast mechanisms' effects can be used as a tracking mechanism to longitudinally evaluate the spatial kinetics of drug movement within the imaging volume.
The tissue contrast changes apparent on an MR image can arise from ADC, from alterations in the BO magnetic field (often referred to as magnetic susceptibility or ABO produced by the presence of a substance in said tissue), from alterations in local tissue T1 relaxation times, from local T2 relaxation times, from T2* relaxation times (which can be created by susceptibility differences), from the magnetization transfer coefficients (MTC is an effect produced by local communication between free water protons and those of nearby macromolecular structures), from the ADC anisotropy observed in oriented matter, and also from local differences in temperature which will affect in varying degrees all of the included tissue contrast parameters. In addition, the delivery of drug can also be tracked from magnetic field frequency shifts caused by the drug or arising from agents (e.g., MR taggants) added with unique frequency shifts from those of the local protons (such as that created from F-19 or fluorine-19 agents found in or added to the drug).
MR imaging of the alterations in the BO magnetic field (also known as imaging of the local magnetic susceptibility) can reveal the spatial distribution of a drug from the interaction of the drug with the otherwise homogeneous magnetic field found in MRI. To enhance the alterations in the magnetic field BO caused by the drug, small amounts of a BO-altering added agent or agents can be added to the drug during delivery. This can include iron oxide particles, or other materials, such as those comprising lanthanide-, manganese-, and iron-chelates. In addition, vehicles containing differing gases (N2, O2, CO2) will also alter the local magnetic field and thus produce a magnetic susceptibility effect which can be imaged.
The invention includes a device for use in conjunction with magnetic stereotaxis guidance and device delivery and a method for MR-guided targeted drug delivery into a patient, such as intracranial drug delivery, intraspinal drug delivery, intrarenal drug delivery, intracardial drug delivery, etc. The MR-visible drug delivery device is guided by magnetic stereotaxis to the target tissue and/or advanced within entrance points to the patient such as periventricular, intracerebroventricular, subarachnoid, intraparenchymal tissues or the cerebrovasculature under magnetic resonance imaging or real time X-ray fluoroscopy, and all of this is possibly also done in conjunction with conventional methods of neurosurgical or neuroradiologic catheter manipulation. The drug delivery device preferably has a linearly arranged array of radiopaque and MR-visible markers disposed at its distal end to provide easily identifiable reference points for trackability and localization under susceptibility MR imaging and X-ray fluoroscopy guidance. Additionally, active MR visualization of the drug delivery device is achieved or enhanced by means of RF microcoils positioned along the distal axis of the device. MR visibility can be variably adjustable based on requirements related to degree of signal intensity change for device localization and positioning, enhancement along the shaft of the device, enhancement around the body of the device, visibility of the proximal and distal ends of the device, degree of increased background noise associated with device movement, and other factors which either increase or suppress background noise associated with the device. Since the tip of the drug delivery device can be seen on MR and X-ray images and thus localized within the brain, the multiple point source locations of drug delivery are therefore known and can be seen relative to the tip or the shaft of the device.
Targeted delivery of drug agents may be performed by any therapeutically effective drug delivery device or system, including, for example, those utilizing MR-compatible pumps connected to variable-length concentric MR-visible dialysis probes each with a variable molecular weight cut-off membrane, or by another MR-compatible infusion device which injects or infuses a diagnostic or therapeutic drug solution. Imaging of the injected or infused drug agent is performed by MR diffusion mapping using the RF microcoils attached to the distal shaft of the injection device, or by imaging an MR-visible contrast agent that is injected or infused through the walls of the dialysis fiber into the brain. The delivery and distribution kinetics of injections or infusions of drug agents at rates, for example, of between 1 μl/min (or less) to 1000 μl/min (or more) are monitored quantitatively and non-invasively using real-time contrast-enhanced magnetic susceptibility MR imaging combined with water proton directional diffusion MR imaging. One aspect of the present invention is to provide a non-invasive, radiation-free imaging system for tracking a drug delivery or other medical device to a target intracranial location in conjunction with or following magnetic stereotaxis manipulation and placement of the drug delivery device in the procedure.
Another aspect of the present invention is to provide an imaging system for visualizing the distal tip of the drug delivery or other medical device at the target intracranial location in conjunction with or following magnetic stereotaxis delivery of the drug delivery device in the procedure.
A third aspect of this invention is to provide for an MR-compatible and visible device that significantly improves the efficacy and safety of intracranial drug delivery using MR guidance in conjunction with or following magnetic stereotaxis delivery of the drug delivery device in the procedure.
A fourth aspect of the present invention is to provide for interactive MR imaging of injected or infused MR-visible drug agents superimposed upon diagnostic MR images of the local intracranial anatomy in conjunction with or following magnetic stereotaxis delivery of the drug delivery device and manipulation and placement of the device in the procedure.
A fifth aspect of the present invention is provide an MR imaging method for quantitative monitoring of the spatial distribution kinetics of a drug agent injected or infused from a drug delivery device into the central nervous system or cerebrovascular system to determine the efficacy of drug delivery at various sites, such as at intracranial target sites.
A sixth aspect of the present invention is to provide for magnetically responsive catheters and other drug delivery devices which can be steered by an applied magnetic field using nonlinear magnetic stereotaxis to provide directional control of the tip of the device to guide the device to targeted intracranial locations.
A seventh aspect of this invention is to provide for a magnetically responsive catheter device which can be steered or navigated through bulk tissues in the brain using nonlinear magnetic stereotaxis with minimal frictional drag and minimal tissue injury.
An eighth aspect of this invention is to provide for a magnetically responsive catheter device which can be guided by nonlinear magnetic stereotaxis to sites of cerebrovascular lesions, including aneurysms, stroke sites, tumors, arteriovenous malformations and fistulae.
A ninth aspect of the present invention is to provide an MR imaging method to evaluate how the spatial distribution kinetics of a drug agent injected or infused from a drug delivery device into the central nervous system is influenced by infusion pressure, flow rate, tissue swelling and other material properties of the brain, and by the physicochemical and pharmaco kinetics nature of the drug or therapeutic agent infused.